Rapaglutins, novel inhibitors of GLUT and use thereof

Abstract

Compounds with the following structuresand their analogs are provided. Compositions that include these structures can be used to inhibit glucose transporters and stop or decrease the proliferation of cancer, treat possible organ rejection and treat autoimmune disease.

What is claimed is: 
     
       1. A compound with the following structure: 
       
         
           
           
               
               
           
         
         wherein residue 1, residue 2, residue 3, and residue 4 are exchanged and selected from below: 
       
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Compound No. 
                   Peptide (residue 1-residue 2-residue 3-residue 4) 
                 
                     
                     
                 
                     
                   A18-2 
                   mGly-mlle-dPhe-mLeu 
                 
                     
                   A18-3 
                   Pro-mIle-dPhe-mLeu 
                 
                     
                   A18-4 
                   dPro-mlle-dPhe-mLeu 
                 
                     
                   A18-5 
                   Gly-mVal-dPhe-mLeu 
                 
                     
                   A18-8 
                   Gly-mNle-dPhe-mLeu 
                 
                     
                   A18-9 
                   Gly-mNva-dPhe-mLeu 
                 
                     
                   A18-10 
                   Gly-mLeu-dPhe-mLeu 
                 
                     
                   A18-15 
                   Gly-mlle-mdPhe-mLeu 
                 
                     
                   A18-16 
                   Gly-mlle-dLeu-mLeu 
                 
                     
                   A18-17 
                   Gly-mlle-dPhe-Leu 
                 
                     
                   A18-18 
                   Gly-mlle-dPhe-mlle 
                 
                     
                   A18-19 
                   Gly-mlle-dPhe-mNva 
                 
                     
                   A18-20 
                   Gly-mlle-dPhe-mNle 
                 
                     
                   A18-21 
                   Gly-mIle-dPhe-mVal 
                 
                     
                   A18-22 
                   Gly-mlle-dPhe-mPhe; 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or 
       
       
         
           
           
               
               
           
         
         wherein residue 1, residue 2, residue 3, and residue 4 are exchanged and selected from below: 
       
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Compound No. 
                   Peptide (residue 1-residue 2-residue 3-residue 4) 
                 
                     
                     
                 
                     
                   E11-72-1 
                   Gly-mSerBu-Nal-mAla 
                 
                     
                   E11-72-2 
                   mGly-mSerBu-Nal-mAla 
                 
                     
                   E11-72-3 
                   Gly-mSer-Nal-mAla 
                 
                     
                   E11-72-4 
                   Gly-HoSerMe-Nal-mAla 
                 
                     
                   E11-72-5 
                   Gly-mSerBu-mPhe-mAla 
                 
                     
                   E11-72-6 
                   Gly-mSerBu-Phe-mAla 
                 
                     
                   E11-71-16 
                   Gly-mSerBu-Nal-Ala 
                 
                     
                   E11-71-17 
                   dPro-mSerBu-Nal-mAla 
                 
                     
                   E11-71-18 
                   Pro-mSerBu-Nal-mAla 
                 
                     
                   E11-71-19 
                   GIy-mLeu-Nal-mAla 
                 
                     
                   E11-71-20 
                   Gly-mPhe-Nal-mAla 
                 
                     
                   E11-71-24 
                   Gly-mSerBu-Nal-mGly 
                 
                     
                   E11-71-25 
                   Gly-mSerBu-Nal-mdAla 
                 
                     
                   E11-71-26 
                   Gly-mSerBu-Nal-Pro 
                 
                     
                   E11-71-27 
                   Gly-mSerBu-Nal-mNva 
                 
                     
                   E11-71-28 
                   Gly-mSerBu-Nal-mPhe 
                 
                     
                   E11-71-29 
                   Gly-mSerBu-Nal-mLeu 
                 
                     
                   E11-71-30 
                   Gly-mSerBu-Nal-mlle 
                 
                     
                   E11-71-31 
                   Gly-mSerBu-Nal-mNle. 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       2. A compound with the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         n is an integer selected from 0 to 6; 
         R 1  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         when R 1  is 
       
       
         
           
           
               
               
           
         
          R 1 ′, R 2 ′, R 3 ′, R 4 ′, and R 5 ′ are independently selected from the group consisting of OH, NH 2 , SH, CN, H, OAc, and OMe, 
         when R 1  is 
       
       
         
           
           
               
               
           
         
          A, B, X, Y, and Z are independently C or N, 
         when R 1  is 
       
       
         
           
           
               
               
           
         
          R 1 ′, R 2 ′, R 3 ′, R 4 ′, and R 5 ′ are independently selected from the group consisting of OH, NH 2 , SH, H, OAc, and OMe, 
         when R 1  is 
       
       
         
           
           
               
               
           
         
          A, X, Y, and Z are independently selected from the group consisting of —(CH)m-, O, N, and S, where m is an integer selected from 1 to 2; 
         R 2 , R 3 , and R 4  are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, phenyl, OH, NH 2 , SH, and CN; 
         R 5 , R 6 , R 7 , and R 8  are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, phenyl, OH, NH 2 , SH, and CN; 
         R 9 , R 10 , R 11 , and R 12  are independently selected from the group consisting of hydrogen and methyl; 
         R 13  and R 14  are independently selected from the group consisting of OH, NH 2 , SH, CN, and hydrogen; 
         “ ” represents a double bond with E or Z configuration; and 
         the amino acids with residues 1 to 4 are selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         or residue 1, 2, 3, or 4 together with the adjacent nitrogen form 
       
       
         
           
           
               
               
           
         
       
     
     
       3. A compound according to  claim 1 , wherein the compound is Formula A18. 
     
     
       4. A compound according to  claim 1 , wherein the compound is Formula E11.